The antitumor effects of two immunotoxins (IT) were evaluated in vitro and in vivo against the human ovarian carcinoma cell line, OVCAR-3. The ITs used were an anti-carcinoma MoAb coupled to Pseudomonas exotoxin (NR-LU-10/PE) and a IT composed of the recombinant A chain of ricin covalently attached to a MoAb directed to the transferrin receptor (454Al2/rRTA). Protein synthesis was inhibited in a dose-dependent manner in OVCAR-3 cells incubated in vitro with either NR-LU-10/PE or 454Al2/rRTA (IC50=1 and 75 ng/ml) respectively. Concomitant incubation in vitro of OVCAR-3 cells with NR-LU-10/PE or 454Al2/rRTA and a non-cytotoxic concentration of rhIFN-alpha was shown to potentiate the inhibitory activity of the ITs via a mechanism distinct from antigenic regulation. Studies showed that the MST of mice injected i.p. with 4,000,000 OVCAR-3 cells was 46 days. Cohorts of mice that received intracavitary treatment beginning five days post-tumor cell injection with either 0.25 or 0.5 (mu)gs of NR-LU-10/PE every other day for a total of ten treatments exhibited significantly increased MSTs of 63.0 and 104 days respectively (P=0.0001). Likewise, the i.p. injection of either 2.5 or 10 (mu)gs of 454Al2/rRTA administered by an identical regimen, resulted in MSTs of 89.0 and >120.0 days, respectively (P=0.0001). When rhIFN-alpha was administered i.p. in conjunction with these doses of either IT, a significant increase in MST was observed in comparison to mice given IT alone. The combination of 50,000 U rhIFN-alpha and 0.25 (mu)gs NR-LU-10/PE resulted in 67% long-term survivors compared to only 13% survival of mice given IT alone. Similarly, 2.5 (mu)gs of 454Al2/rRTA plus rhIFN-alpha resulted in 89% long-term survivors compared to 454AI2/rRTA alone (29%). Preliminary studies have revealed that a human colon line expressing the MDR gene, Ht-29(R), is highly resistant to multiple i.p. treatments of vincristine (2mg/kg). Investigations are underway to attempt to reverse this resistance in vivo utilizing various drugs and biological agents.